A Cancer Target Pulls a 180

Scientists will be the first to admit that science sometimes makes mistakes. Though debates and changing theories are often seized upon by everyone from anti-vaxxers and climate change skeptics as flaws in the scientific process, the constant revision is actually the key to science’s strength, gradually building accuracy through trial and constructive error. Still, it’s frustrating when a particular biomedical theory fails to pay off in the clinic, and more so when additional data spins the entire theory around.

Such a reversal may have occurred this week with the publication in Nature of a cancer research paper by University of Chicago and Northwestern University scientists. The research project, a collaboration between the laboratories of Marcus Peter (now of Northwestern University Feinberg School of Medicine) and Ernst Lengyel, looked at CD95, known to be one of the cellular “death receptors.” That intimidating nickname comes from CD95’s role in apoptosis, the self-destruct mode triggered by a cell when it is damaged or under attack.

If CD95 was so good at killing cells, it followed that activating the receptors would be a potential strategy for treating cancer, where the problem is unrestrained cell division and resistance to apoptosis. But the new Nature study finds evidence for the mirror image of that conclusion: Activating CD95 actually fuels the growth of cancer cells.

“This is a paradigm-shifting discovery,” said Lengyel, associate professor of medicine at the University of Chicago Medical Center. “For 20 years, scientists have tried to use CD95 to kill tumors, but what we showed is that it is actually promoting tumor growth.”

With laboratory experiments conducted on cell lines and mouse models of cancer, the research team showed repeatedly that cancer growth was slowed by removing or inhibiting CD95, not activating it. That explains a mystery that has always hurt the original CD95-cancer theory: if the receptor is so deadly to cancer cells, why do they express so many of them? The researchers concluded that the function of CD95 must somehow turn traitor when cells become cancerous, flipping a death receptor into a growth receptor. As an accompanying editorial by Douglas Green of St. Jude’s Children’s Research Hospital said, CD95 is a “wolf in wolf’s clothing.”

“A general role for autocrine CD95 signalling in promoting cancer is a stunning revelation that goes against many of the prevailing notions of what this receptor does,” Green said. “There is our realization that this ‘wolf,’ this potentially vital tumour-promoting mechanism, has been there all along, disguised as a mechanism of cell death.”

Fortunately, there is already a drug candidate for employing this reversed CD95 strategy against cancer. One way to block CD95 activity would be to block the ligand that activates the receptor, and a German company has developed a “soluble receptor” that soaks up CD95’s ligand like a sponge. Though currently being tested for the treatment of AIDS and degenerative diseases, Peter and Lengyel’s data suggests potential for cancer as well.

“This will be a big translational project, and it is years away from coming to the clinic,” Lengyel said. “But there are two ways that it might be used to treat patients: either using a soluble receptor that will sweep away the ligand before it binds cells and promotes growth, or by using an antibody against this ligand to block its activity.”

Beyond it’s potential for medical application, the CD95 story also shows how it’s very difficult to convince the march of science to change course. “Sometimes…a viewpoint becomes so ingrained in our collective scientific consciousness that alternatives go unheeded,” Green wrote in his editorial about prior hints that CD95 might be working differently in tumors. But when science is convinced that it may have made a mistake, it’s generally for the best – getting on the right track is always better late than never.